Mouse Hepatitis Virus Receptor as a Determinant of the Mouse Susceptibility to MHV Infection

Taguchi, Fumihiro; Hirai-Yuki, Asuka

If the differing susceptibilities between CEACAM1a-expressing mice and SJL with CEACAM1b are determined by CEACAM1, then MHV-susceptible mice with CEACAM1a are converted to SJL type-resistant mice, when the Ceacam1a mouse gene is replaced with a Ceacam1b gene. We have produced C57BL/6 (B6) mice whose original Ceacam1a gene is replaced by a Ceacam1b gene (Hirai et al., 2010) . Since it has been revealed that the chimeric CEACAM1a, which is replaced with 1-70 amino acids of the N terminus of N domain with CEACAM1b counterpart, functioned as CEACAM1b, suggesting that there is a critical region in 1-70 amino acids to determine the difference of receptor functionality between CEACAM1a and CEACAM1b (Wessner et al., 1998) . Thus, we produced B6 mice whose N terminal region (1-70 amino acids) is replaced by CEACAM1b (we call it CEACAM1ba) to see the mouse susceptibility is determined by CEACAM1. CEA-CAM1ba has two N-linked glycosylation sites in the N domain as CEACM1b, while CEACAM1a has three sites, showing that chimeric CEACAM1ba is more like CEACAM1b rather than CEA-CAM1a. Those gene-replaced mice expressed the chimeric protein in the tissues or cells where CEACAM1a and CEACAM1b were expressed in B6 and SJL mice, respectively. It was also revealed that there is no significant difference in the expression level of CEACACM1a and CEACAM1ba in B6 and chimeric B6 mice (Hirai et al., 2010) . Additionally, the chimeric CEACAM1 did not react with the CEACAM1a-specific monoclonal antibody, CC1 as reported previously (Wessner et al., 1998) . We then examined the susceptibility of mice having a chimeric Ceacam1. The gene-replaced mice, when compared to B6 mice, were resistant to a lethal dose of MHV-A59 infection, a finding similar to those in SJL mice that were resistant to the infection. However, when we examined virus growth in B6, SJL, and the gene-replaced mice, high titer of MHV were detected in the liver and other target tissues of B6 mice, while low levels of virus titer were recorded in SJL mice, findings which are similar to the results we have thus far obtained. Interestingly, no virus growth was detected in the mice having gene-replacement with chimeric CEACAM1, indicating the gene-replaced mice showed a much higher resistance to MHV infection than did the SJL mice. Since the virus-binding domain is derived from SJL, the chimeric mouse susceptibility should be similar to that in SJL mice, if our hypothesis is correct. However, at the moment, we have no convincing explanation on the difference in susceptibility of SJL and chimeric mice with identical MHV-binding site on CEACAM1.